Targeted radionuclide-drug conjugates: Current status and perspectives.

Abstract

Radionuclide drug conjugates (RDCs) are emerging molecular platforms for diagnostic imaging, targeted radionuclide therapy, and precision-oncology theranostics. Theranostic applications typically employ matched diagnostic and therapeutic radionuclides conjugated to the same or closely related targeting scaffolds. An RDC generally comprises a targeting ligand, a linker, a chelator, and a radionuclide, thereby enabling selective tumor targeting for either diagnostic imaging or targeted radiotherapy depending on the conjugated radionuclide. This review summarizes recent advances in RDC design, with particular emphasis on radionuclide selection, linker chemistry, and ligand-engineering strategies. Clinically relevant molecular targets, including prostate-specific membrane antigen (PSMA), somatostatin receptors (SSTRs), cholecystokinin-2 receptor (CCK2R), gastrin-releasing peptide receptor (GRPR), and fibroblast activation protein (FAP), are discussed alongside representative diagnostic, therapeutic, and theranostic platforms. These platforms include ⁶⁸Ga/¹⁷⁷Lu-PSMA systems, ⁶⁸Ga/¹⁷⁷Lu-DOTATATE or OPS202/OPS201 pairs, ⁶⁸Ga/¹⁷⁷Lu-NeoBOMB1, and ¹⁸F/¹⁷⁷Lu-fibroblast activation protein inhibitor (FAPI) systems. Despite their potential to improve patient stratification and therapeutic efficacy while reducing systemic toxicity, RDCs face substantial challenges, including tumor heterogeneity, radiochemical instability, renal toxicity, and constraints on the large-scale production of radionuclides. Future advances will depend on the development of multitargeting strategies, novel radionuclides, and artificial intelligence (AI)-assisted rational design.